In the fields of pharmaceuticals, foods and other chemical engineering and the like, it has been a general practice conventionally to prepare a molded body containing an active ingredient using cellulose particles such as crystalline cellulose, cellulose powder and the like as an excipient, and for these cellulose particles, good compactibility, fluidity and disintegration property are required.
Patent Document 1 describes a porous cellulose aggregate (corresponding to Comparative Example 15-17) having a secondary aggregate structure formed by aggregation of primary cellulose particles, the aggregate having a pore volume within a particle of 0.265 cm3/g to 2.625 cm3/g, containing type I crystals, and having an average particle size of more than 30 μm and 250 μm or less, a specific surface area of 1.3-20 m2/g, a repose angle of 25° or more and less than 44° and properties to disintegrate in water, and a method for producing the aforementioned porous cellulose aggregate comprising a step of drying a dispersion containing two or more groups of primary cellulose particles having a different average particle size and a liquid medium wherein the cellulose dispersion particles have an average particle size of 1 to 110 μm. Since the aforementioned porous cellulose aggregate of the Patent Document requires two or more groups of primary cellulose particles having a different average particle size, different primary cellulose particles prepared by two processes such as grinding dried acid insoluble residue of commercially available pulp and the like have to be mixed as described in Example of the Patent Document. On the other hand the porous cellulose particles of the present invention can be obtained advantageously with a single process without going through a process of grinding or the like. The porous cellulose aggregates of the present invention can be obtained by a single process by making the primary cellulose particles to have a specified range of average width and average thickness and by making flexible, thereby promoting entanglement of primary cellulose particles without being limited by the major axis of the primary cellulose particles, in other words by giving self aggregation ability thereto, and are clearly different from that described in the Patent Document in terms of the production method. In addition, because the pore size of the secondary aggregate structure of the porous cellulose particles according to the Patent Document is smaller than that of the porous cellulose aggregates of the present invention, and the swelling degree is lower in water, the disintegration property is sometimes not sufficient for making tablets for a formulation that severely requires disintegration property in the case of drugs which is insoluble in water, and even in the case of soluble drugs, when a water repellent additives such as magnesium stearate and the like has to be added to avoid problems in tablet pressing such as sticking and the like. We have investigated in detail the particle structure which controls disintegration property, and as a result confirmed again that the cellulose particles having a high swelling property have a high disintegration property, and we realized that for conventional cellulose powder, if the swelling property is high, the compactibility is not sufficient, and conversely if the compactibility is high, the swelling property is low. That is, no cellulose powder having both a high compactibility and high swelling property has been known. We searched for a method to make the particles porous while keeping the pore diameter of porous cellulose particles as large as possible and have managed to solve the aforementioned problem. That is, we found that excess aggregation can be controlled, and the inside of the particles can be made porous while keeping the pore diameter large by using primary cellulose particles having a specified range of average width and average thickness and giving self-aggregation ability thereto. For the porous cellulose aggregates of Patent Document 1, it is described that when two or more groups of cellulose particles having different particle size are mixed, and the cellulose dispersion is dried, the dispersed cellulose particles having a small average particles size enter between the dispersed cellulose particle components having a large average particle size, and for this reason an excess aggregation of the dispersed cellulose particles having the larger average particle size is inhibited, and a large pore volume is created in the secondary aggregate structure. However, since tight aggregation is formed among two or more groups of cellulose having different average particle size, the pore diameter of the porous cellulose aggregates obtained by the method particularly disclosed in the Example was measured to be small, about 1.5 μm. Since the porous cellulose aggregate of the present invention uses the single primary cellulose particles, they are not aggregated as tightly as the porous cellulose aggregate of the Patent Document and they are different in having a minimum 3 μm pore diameter. For the size of pore diameter, the Patent Document describes that a clear peak can be recognized in the range of 0.1-10 μm and the median pore diameter, which is a peak top of the pore distribution and closely related to water permeability into the particles, is preferably 0.3 μm or larger, and that although a larger median pore diameter is better, it is at most 5 μm considering its distribution. It is described that with a larger median pore diameter, there is better disintegration property, but it is speculated that in practice it is difficult to obtain a large median pore diameter of 3 μm or larger by the production method according to the Patent Document. The porous cellulose aggregates of the present invention has an advantage that porous cellulose aggregates having a large median pore diameter of 3 μm or above, which can not be obtained by the production method of the Patent Document, can be prepared by a single step without requiring mixing of the different primary cellulose particles prepared through two steps.
Patent Document 2 describes porous cellulose particles (corresponding to Comparative 6 of the present application) having a crystal structure type I, having pores of diameter of 0.1 μm or above and a porous rate of 20% or above and containing 90% by weight or above of a fraction with 350 mesh and above, which is obtained by mixing cellulose particles with the third component such as a crystalline compound or the like that is insoluble or hard to be soluble in water but soluble in an organic solvent, by granulating and drying the mixture using water or a water soluble organic solvent and then extracting/removing the third component with an organic solvent. The porous cellulose particles described in this document is entirely different from the porous cellulose aggregates of the present invention in the particle structure, because the primary cellulose particles form such a homogeneous continuous film-like tight strong cellulose wall structure that the boundaries of the particles become unclear. Although the cellulose particle in Patent Document 2 is superior in its fluidity, the tight continuous cellulose wall is impermeable to water, so that the cellulose particle was not disintegrated in water, and sometimes the rapid release of an active ingredient was impeded. Further, the cellulose particle of Patent Document 2 is poor in its plastic deformation and has insufficient compactibility while the cellulose is compressed, and furthermore since an organic solvent and a third component, which is a crystalline compound soluble in the organic solvent, are used during the production process, not only the production cost is high but also the active ingredient can be inactivated. Thus it is insufficient to be used stably as an excipient.
Patent Document 3 describes porous micro-cellulose particles (corresponding to Comparative Example 7 of the present application) having a porous structure with crystal structure type I, a specific surface area of 20 m2/g of above and a pore volume of 0.3 cm3 or above for pores with diameter 0.01 μm or larger, and having an average particle size of at most 100 μm, obtained by granulating and drying fine particle natural cellulose dispersed in an organic solvent using spray-dry method. These micro-cellulose particles also have the aforementioned cellulose wall structure and are entirely different from the porous cellulose aggregates of the present invention in the particle structure. Further, the pore volume itself of the cellulose particles of Patent Document 3 is large, but since the particle structure is different from that of the porous cellulose aggregates of the present invention, water permeation into the particles is difficult, and there is a problem of the inferior disintegration property. In addition, since an organic solvent is used for these porous cellulose aggregate particles during the production process, not only is the production cost high but also the active ingredient can be inactivated because the specific surface area is too large and the interaction between the active ingredient and water is promoted. Thus it is insufficient to be used stably as an excipient.
Patent Document 4 describes cellulose powder (corresponding to Comparative Example 8 of the present application) having an average degree of polymerization of 150-375, apparent specific volume of 1.84-8.92 cm3/g, a particle size of 300 μm or less as cellulose powder having a good compactibility and disintegration property.
Patent Document 5 describes micro-crystalline cellulose aggregates (corresponding to Comparative Example 9 of the present application) having an average degree of polymerization of 60-375, apparent specific volume of 1.6-3.1 cm3/g, apparent tapping specific volume of 1.4 cm3/g or above, a repose angle of 35-42°, and containing 2-80% by weight of component of 200 mesh or above. The cellulose powder obtained according to Examples of these Patent Documents has a small intraparticular pore volume according to the measurement result of pore distribution using mercury porosimetry and the pore structure is entirely different from that of the present invention which is formed intentionally. For that reason, these cellulose powders have a small specific surface area of 0.6-1.2 cm3 and poor compactibility. These publications disclose the control of the compactibility, fluidity and disintegration property of cellulose particles by adjusting the apparent specific volume, but there were problems that in the range of relatively small apparent specific volume of 2.0-2.9 cm3/g, the fluidity and disintegration property were good but the compactibility was unsatisfactory, while with larger apparent specific volume of 3.0-3.2 cm3/g, the compactibility was good but the fluidity and disintegration property were poor.
Patent Document 6 describes β-1,4-glucan powder (corresponding to Comparative Example 1 of the present application) as cellulose powder having good compactibility having an average particle size of at most 30 μm and a specific surface area of 1.3 m2/g. The β-1,4-glucan powder described in the document does not have the secondary aggregate structure, and individual primary particles exist singly. Although this glucan powder has good compactibility, it has problems that the disintegration property is poor and the fluidity is inferior due to the small average particle size.
Patent Document 7 describes a cellulose powder (corresponding to Comparative Example 10 of the present application) having an average degree of polymerization of 100-375, an acetic acid retention rate of 280% or above, Kawakita formula (P*V0/(V0−V)=1/a*b+P/a) wherein a is 0.85-0.90, b is 0.05-0.10, an apparent specific volume of 4.0-6.0 cm3/g, substantially no particles of 355 μm or larger, and an average particle size of 30-120 μm as a cellulose powder having good compactibility and disintegration property obtained by hydrolyzing a cellulose-like substance. The cellulose powder obtained by the method of Example described in that document has also a small pore volume within a particle according to the measurement result of pore distribution using the mercury porosimetry and thus the pore structure is entirely different from the intentionally formed pore structure of the present invention. Although the cellulose powder of Patent Document 7 is described to have good compression compactibility and disintegration property, the best balanced Example that is disclosed specifically is measured to have a repose angle of over 55° and the fluidity is not satisfactory enough. There was a problem that in formulations, in which an active ingredient having poor fluidity was used in large proportion, the variation coefficient of tablet weight was larger thereby influencing uniformity of the drug content. Further, when compacting (molding) was performed under high pressure using the cellulose powder according to the document, a high hardness can be obtained but there was a problem of delayed disintegration because there is no intentionally formed intraparticular pore, and water permeability to inside of the particle was low.
Patent Document 8 describes a crystalline cellulose (corresponding to Comparative Example of 11 of the present application) as the cellulose powder having good compactibility, disintegration property and fluidity, which has an average degree of polymerization of 100-375, and in which the particles that pass through a 75 μm sieve and are retained on a 38 μm sieve occupy 70% or more of the total weight, and an average major axis and minor axis ratio of the particles is 2.0 or higher.
Patent Document 9 describes a cellulose powder (corresponding to Comparative Example of 2-4 of the present application) as the cellulose having good compactibility, disintegration property and fluidity, having an average degree of polymerization of 150-450, an average L/D (ratio of major axis/minor axis) of 2.0-4.5 for particles of 75 μm or less, an average particle size of 20-250 μm, an apparent specific volume of 4.0-7.0 cm3/g, and a repose angle of 54° or less and a specific surface area of 0.5-4 m2/g. Since the pore volume within a particle of the cellulose powders described in these publications, similar to the cases described above, measured by the mercury porosimetry is small, the cellulose have entirely different pore structure from the intentionally formed pore structure of the present invention. The cellulose powders described in these publications give a high hardness to a molded body by elongating the shape of particles, but because they have an elongated shape, the apparent specific volume becomes larger, and the higher the compactibility, the fluidity decreases. Among the cellulose powders in Examples described in these publications, the one having the best fluidity was measured to have a repose angle of 44°. For example, when continuous compression was performed at high speed in a formulation in which an active ingredient having poor fluidity was mixed in a large proportion, the variation coefficient of tablet weight was getting larger, thereby influencing uniformity of the drug content, and thus satisfactory result was not obtained in terms of fluidity. Further, when compacting (molding) was performed under high pressure using the cellulose powder according to these publications, high hardness can be achieved but there was a problem of delayed disintegration because there was no intentionally formed intraparticular pore, and water permeability to the inside of particle was low.
Patent Document 10 describes a cellulose powder (corresponding to Comparative Example 14 of the present application) having an average degree of polymerization of 150-450, an average particle size 30-250 μm, an apparent specific volume of over 7 cm3/g and a holding capacity of polyethylene glycol with a molecular weight of 400 of 190% or more. The cellulose powder of this document does not hold a secondary aggregate structure, and primary cellulose particles exist substantially as a singlet. Also, the intraparticular pore volume measured by the mercury porositometry is small and the cellulose powder has an entirely different pore structure from the intentionally formed pore structure of the present invention. Further, when the apparent specific volume is large, the fluidity is greatly impaired, and the repose angle of the best cellulose powder in terms of fluidity according to this document was measured to be 50°. For example, when continuous compacting (molding) was performed at high speed in a formulation in which an active ingredient having poor fluidity was mixed in a large proportion, the variation coefficient of tablet weight was increased, thereby influencing uniformity of the drug content, and thus satisfactory result was not obtained in terms of fluidity. Further, when compacting (molding) was performed under high pressure using the cellulose powder according to the document, high hardness can be achieved but there was a problem of delayed disintegration because there was no intentionally formed intraparticular pores, and water permeability to the inside of particle was low.
In addition, the average particle size of the dispersed cellulose particles in the cellulose dispersion must be 50 μm or larger to increase the apparent specific volume, but the average particle size of the dispersed cellulose particles of the present invention is obtained at 10 μm or larger and less than 50 μm, which is quite different in terms of the production method.
In the range of 2.3-6.4 cm3/g of the apparent specific volume for the cellulose powders described in these Patent Documents 6-9, and in the range of over 7 cm3/g of the apparent specific volume for the cellulose powders described in Patent Document 10, sufficient compactibility was obtained in each case but there was a problem that the fluidity and disintegration property were deteriorated.
Patent Document 11 describes pharmacologically inert round shaped seed core containing 10-70% of a crystalline cellulose having an average degree of polymerization of 60-375 and 10-90% of a water soluble additive as cellulose particles having good fluidity. Further, Patent Document 12 describes a pharmacologically inert round shaped seed core (corresponding to Comparative Example 12 of the present application) containing 50% or more of a crystalline cellulose having a water absorbing capacity of 0.5-1.5 ml/g, roundness of 0.7 or higher, an apparent tapping specific volume of 0.65 g/ml or higher, a friability of 1% or less and an average degree of polymerization of 60-375, wherein distilled water is added to powder containing crystalline cellulose at 50% or more while mixing using a mixer granulator and kneaded to prepare the round shaped seed core. Patent Document 13 describes microcrystalline cellulose particles having a loose bulk density of at least 0.4 g/cm3 (2.5 cm3/g in apparent specific volume), spherical shape, an average particle size of 2-35 μm and a smooth surface, wherein the microcrystalline cellulose particles is prepared by mechanically reducing the particle size of hydrolyzed cellulose particles and by spray-drying. Patent Document 14 describes cellulose system particles (corresponding to Comparative Example 13 of the present application) containing 10% or more of the crystalline cellulose having an average degree of polymerization of 60-350, and having an apparent tapping specific volume of 0.60-0.95 g/ml, roundness of 0.7 or higher, a shape coefficient of 1.10-1.50, and an average particle size of 10-400 μm, wherein the crystalline cellulose is obtained by hydrolyzing a cellulose material to an average degree of polymerization of 60-350, then grinding the result mechanically to the average particle size of 15 μm, and then drying the dispersion containing thus obtained crystalline cellulose in a shape of liquid droplets.
The cellulose particles described in these documents do not form a secondary aggregate structure, and the celluloses obtained by the method of Examples described in Patent Documents have an apparent specific volume of 2.5 cm3/g or lower, nearly spherical shape and good fluidity but are poor in compression compactibility, and under the commonly used compression pressure of 10-20 MPa, a molded body which has sufficient hardness for practical use can not be made.
As described above, for cellulose particles of conventional arts, compactibility, fluidity and disintegration property have been mutually contradictory characteristics, and it has been hoped to obtain cellulose particles having these characteristics in good balance.
On the other hand, since the cellulose particles described in Patent Documents 4-9, and 11-14 do not have intraparticular pores that are intentionally formed, and pore volume within a particle is small, almost no active ingredient can be held in the particles and therefore there have been problems of liquid components bleeding out in compression compacting (molding) and problems in tablet press operation. Also, the cellulose particles described in Patent Document 2 and 3 have intraparticular pores, but the pore diameter is small, and therefore it is difficult for water to permeate into the dense and continuous cellulose wall, which imposes problems that the cellulose particle does not disintegrate in water and quick release of an active ingredient is hindered. The cellulose particles described in Patent Document 10 has an apparent specific volume that is too big, and especially in high speed compression compacting (molding) they sometimes cannot be practically used because of the their fluidity and disintegration property.
Furthermore, since these cellulose particles do not have intraparticular pores that are intentionally formed, and the pore volume within a particle is small, almost no active ingredient can be held in the particles, and thus they have a shortcoming that in solid formulation of an active ingredient that is hard to be soluble in water, the formulation can not be practically used due to slow elution of the active ingredient, unless complicated processes are performed such as temporary granulation with water or an organic solvent, drying and the like. They also have a shortcoming that in solid formulation of an active ingredient that tends to sublimate, the active ingredient re-crystallizes during storage, ruining their commercial value.
The active ingredient in a solid formulation for oral administration is eluted from the formulation to the body fluid in the digestive tract, absorbed from the digestive tract, enters into the blood circulation and expresses the drug effect. Since the active ingredient that is hard to be soluble in water is poorly eluted, sometimes it is excreted out of the body before all the administered active ingredient is eluted and full effect is not expressed. The ratio of the total amount of active ingredient entering into the blood circulation to the administered amount of active ingredient is generally known as bioavailability, and to improve bioavailability and the rapid action of active ingredient, various methods have been investigated up until now for improving the elution of hardly-soluble active ingredients.
Patent Document 15 describes a method for grinding an active ingredient that is hard to be soluble in water and β-1,4-glucan powder together. This method needs a long time for grinding treatment until crystalline characteristics of β-1,4-glucan powder are lost, and also powerful shear must be applied continuously for a long time using a roll mixer, thus creating a problem of poor efficiency in the actual production process. Further, β-1,4-glucan powder that has lost the crystalline characteristics has a problem of poor compression compactibility.
For a solid formulation for oral administration prepared by the direct press method from a main drug that is hard to be soluble in water, Patent Document 16 describes a method for increasing the disintegration of the tablet and the rate of elution of the main drug by increasing the hardness of the tablet and decreasing the variation of the main drug content by adding β-1,4-glucan, a disintegrator and a surfactant. This document describes no intraparticular pores, and it is not known at all to improve water solubility of a drug by mixing an active ingredient that is hard to be soluble in water and a porous cellulose aggregate. Furthermore, since a surfactant has to be added to facilitate the elution of the active ingredient that is hard to be soluble in water, there is a problem that when this solid formulation was administered, the surfactant caused inflammation of the mucus membrane of the digestive tract.
Further, Patent Document 17 describes that when tablets are produced by the wet press method using a main drug that is hard to be soluble in water and β-1,4-glucan through the steps of powder mixing, kneading, granulation and drying, tablets having a high tablet hardness, a short disintegration time and a fast elution rate of the main drug can be produced by adding a water soluble polymer solution. Also, this document describes no porous cellulose particle having large intraparticular pores, and it is not known at all to improve water solubility of a drug by mixing an active ingredient that is hard to be soluble in water and a porous cellulose aggregate. Still further in such a method, many steps are essential for drying and there are problems of the cost related to the equipment, and that the energy cost for drying is high. Also, there are problems that this method cannot be applied to an active ingredient inactivated by heat and the like problems.
Patent Document 18 describes a method for improving the elution of a drug by mixing a hardly-soluble drug with porous structured cellulose particles having a particular specific surface area and a pore volume, which is obtained by granulating and drying fine particle like natural cellulose dispersed in an organic solvent by the spray dry method, and absorbing thereto by sublimation. Since the porous cellulose particles described in that document have a high specific surface area and a large pore volume within a particle, the improvement of elution is sure to be observed when the hardly-soluble active ingredient is absorbed by sublimation. However, Example of this Patent Document uses cellulose particles having excessively high specific surface area and the active ingredient absorbed on the surface by sublimation is amorphous and therefore there is a problem of storage stability because during the storage a part of the active ingredient is crystallized and the elution rate is changed, and in a tightly bound compacting composition such as a tablet, there is a shortcoming that the elution of the active ingredient is slow because its disintegration is impeded due to the poor disintegration property.
A sublimatable active ingredient has a problem of bleeding out of a solid formulation during storage, and to prevent this from happening, many of these solid formulations are film coated or sugar coated. However, even with such treatments, there are problems that the active ingredient bleeding out of the formulation through the film layer causes low uniformity of the active ingredient content in the formulation, the active ingredient attached to the surface of the formulation gives irritating smell when taking the formulation or re-crystallizing in a preserving container such as a vial greatly reduces the commercial value. When the coating treatment is not performed on the formulation, the sublimation-re-crystallization is more pronounced than when the coating treatment is performed.
As already described above, in Patent Document 18 cellulose particles having excessively high specific surface area was used, and since the active ingredient absorbed by sublimation on the surface was amorphous, there was a problem of poor storage stability of the active ingredient, and in a tightly bound compacting composition such as a tablet, there was a shortcoming that the elution of the active ingredient was slow because its disintegration was impeded due to the poor disintegration property.
Also, as a method for preventing the re-crystallization caused by sublimation of ibuprofen in solid formulation, Patent Document 19 describes a method for preserving ibuprofen containing solid formulation together with 1 or plurality of stabilizers selected from the group consisting of polyvinyl pyrrolidone, magnesium oxide and sodium bicarbonate in a closed container such as a vial. Using this method the deposition of crystals to the original closed container that has preserved the formulation and the irritating smell of the formulation are surely improved, but polyvinyl pyrrolidone, magnesium oxide, sodium carbonate and the like have to be placed in the container as separate formulations, making the process more complicated, and thus this is entirely different from a single formulation which is made sublimation-proof by adding to the formulation a porous cellulose such as the formulation of the present invention containing a sublimatable active ingredient.
In the past, a composition containing an active ingredient that was oily, liquid or semi solid at normal temperature had problems compared to a solid active ingredient that it is especially prone to tablet pressing problems due to the liquid component bleeding out from the formulation, spots of the liquid component are produced on the surface of the formulation, and in the case of granular formulation, inferior fluidity occurred. These problems not only markedly lower the quality of the product but also cause the low uniformity of the concentration and effect of the active ingredient, and thus improving these problems is a very important task.
In the production of tablets, Patent Document 20-31 describe a method for retaining an active ingredient that is liquid/semi solid at normal temperature to an absorption carrier as it is, or holding an active ingredient dissolved, emulsified or suspended in water, organic solvent, oil, aqueous polymer or surfactant to an absorption carrier, and then compression compacting dried powder or granules obtained after a drying step. However, by the methods of these Patent Documents, the active ingredient that is liquid or semisolid at normal temperature effuses out at the time of compression, causing tablet pressing troubles, and sometimes satisfactory compression molded body may not be obtained. Also, for cellulose particles these Patent Documents do not describe a pore volume within a particle, and it is not known that when the active ingredient that is liquid or semisolid at room temperature is compressed, the addition of the porous cellulose particles of the present invention having a large pore volume within a particle prevents bleeding out by the porous cellulose aggregate holding the active ingredient that is liquid or semisolid inside of the particles and makes preparation of solid formulations such as powder, granules, tablets and the like easier. Still further, in the method described in Patent Document 20-31 many steps are essential for drying and there are problems that the cost related to the equipment, and the energy cost for drying is high.    Patent Document 1: International Patent Application No. 2005/073286 Pamphlet    Patent Document 2: JP-A-1-272643    Patent Document 3: JP-A-2-84401    Patent Document 4: JP-B-40-26274 (CA 699100 A)    Patent Document 5: JP-A-53-127553 (U.S. Pat. No. 4,159,345 A)    Patent Document 6: JP-A-63-267731    Patent Document 7: JP-A-6-316535 (U.S. Pat. No. 5,574,150)    Patent Document 8: JP-A-11-152233    Patent Document 9: International Patent Application No. 02/02643 Pamphlet (US20040053887 A1)    Patent Document 10: International Patent Application No. 2004/106416 Pamphlet (EP1634908)    Patent Document 11: JP-A-4-283520    Patent Document 12: JP-A-7-173050 (U.S. Pat. No. 5,505,983), U.S. Pat. No. 5,384,130)    Patent Document 13: JP-A-7-507692 (U.S. Pat. No. 5,976,600 A)    Patent Document 14: International Patent Application No. 02/36168 Pamphlet (US20040043964 A1)    Patent Document 15: JP-B-53-22138 (U.S. Pat. No. 4,036,990 A)    Patent Document 16: JP-A-53-044617    Patent Document 17: JP-A-54-052718    Patent Document 18: JP-A-03-264537    Patent Document 19: JP-A-08-193027    Patent Document 20: JP-A-56-7713    Patent Document 21: JP-A-60-25919    Patent Document 22: JP-A-61-207341    Patent Document 23: JP-A-11-193229 (EP972513 B1)    Patent Document 24: JP-A-11-35487    Patent Document 25: JP-A-2000-16934    Patent Document 26: JP-A-2000-247869    Patent Document 27: JP-A-2001-181195    Patent Document 28: JP-A-2001-316248    Patent Document 29: JP-A-2002-534455 (U.S. Pat. No. 6,630,150)    Patent Document 30: JP-A-2003-161    Patent Document 31: JP-A-2003-55219